1. Field of the Invention
The present invention relates to methods of producing carboxylic acid ester derivatives of formulae (I) and (II), which are useful, for instance, as intermediates for producing an anti-hypercholesterolemic agent having an inhibitory effect on 3-hydroxy-3-methylgulary-CoA Reductase (hereinafter referred to as HMG-CoA Reductase), in particular, through deprotection or the like. The present invention also relates to intermediates for use in the methods of producing the carboxylic acid ester derivatives: ##STR3## wherein R.sup.1 and R.sup.2 are independently a protective group for hydroxyl group, or R.sup.1 and R.sup.2 integrally constitute a protective group for hydroxyl groups; R.sup.3 is an alkyl group having 1 to 12 carbon atoms, or an aryl group; and R.sup.4 is a substituted aryl group, a substituted heterocyclic group, a substituted vinyl group, or a substituted cycloalkenyl group. ##STR4## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are respectively the same as defined in the above formula (I).
2. Discussion of Background
Compounds having as a substituent an (E)-3,5-dihydroxy-6-heptenoic acid moiety which is bonded thereto at the 7-position thereof, which are hereinafter referred to as 7-position-substituted (E)-3,5-dihydroxy-6-heptenoic acid compounds, serve as HMG-CoA Reductase inhibitors. Many methods of synthesizing such 7-position-substituted (E)-3,5-dihydroxy-6-heptenoic acid compounds, including the methods of synthesizing optical active compounds thereof, have been reported.
The substituent at the 7-position of the (E)-3,5-dihydroxy-6-heptenoic acid moiety of the above-mentioned 7-position-substituted (E)-3,5-dihydroxy-6-heptenoic acid compounds (hereinafter referred to the 7-position substituent) is a key substituent for the generation of the inhibitory activity against the HMG-CoA Reductase. Examples of such a 7-position substituent include a substituted aryl group, a substituted heterocyclic group, a substituted vinyl group, and a substituted cycloalkenyl group.
Methods of introducing the 3,5-dihydroxy-6-heptenoic acid unit into this 7-position substituent can be roughly classified into the following three methods:
(I) A method of introducing a C3 carbon chain into the 7-position substituent, followed by the introduction of a C4 carbon chain. As the C3 carbon chain, 2-propenal or a 2-propene acid derivative is employed in this method.
This method includes, for instance, the following specific methods:
(I-1) A method of introducing as the C4 carbon chain a .beta.-keto ester (J. Med. Chem. 1986, 29, 170, J. Org. Chem. 1991, 56, 5752).
(I-2) A method of introducing as the C4 carbon chain a C2 carbon chain for asymmetric induction, followed by the introduction of a C2 carbon chain (Tetrahedron Lett, 1984, 25, 5031).
(I-3) A method of introducing as the C4 carbon chain an optical active C4 carbon chain which is derived from isoascorbic acid through complicated steps (Tetrahadron Lett, 1985, 26, 2951).
(II) A method of introducing a C1 carbon chain into the 7-position substituent structure, followed by the introduction of a C6 carbon chain.
This method includes, for instance, the following specific methods:
(II-1) A method of allowing a formyl group introduced into the 7-position substituent to react with an optically active Horner-Emmons Reagent having a C6 carbon chain (J. Med. Chem. 1987, 30, 1858).
(II-2) A method of utilizing a substituted sulfinylmethyl group introduced into the 7-position substituent (Tetrahadron Lett. 1985, 25, 2947).
(II-3) A method of utilizing the Witrig reagent or Horner-Emmons reagent converted from the halomethyl group introduced into the 7-position substituent (Tetrahadron Lett. 1982, 23, 4305, Tetrahadron Lett. 1990, 31, 2545).
(III) A method of directly introducing a C7 carbon chain in the 7-position substituent or utilizing a halide compound serving as the 7-position substituent.
This method includes, for instance, the following specific methods:
(III-1) A method of utilizing Heck-Reaction employing a C7 carbon chain having a carbon-carbon unsaturated bond at the terminal thereof (J. Med. Chem. 1990, 33, 31).
(III-2) A method of utilizing the reaction between a silyl-substituted epoxy compound having a C7 carbon chain and an anion species prepared from a halide compound (Tetrahedron Lett. 1992, 33, 4183).
(III-3) A method of utilising a Heck type reaction between a tin-olefin compound synthesized from the above-mentioned silyl-substituted epoxy compound having a C7 carbon chain and a halide compound (Tetrahadron Lett. 1992, 33, 4183).
None of the above-mentioned methods, however, is suitable for industrial production of the 7-position-substituted (E)-3,5-dihydroxy-6-heptenoic acid compounds because of the following respective shortcomings:
In the methods (I-1), (I-2) and (I-3), and (II-1), a reduction reaction which is apt to cause problems with respect to the reproducibility thereof is required at a stage close to the final stage of the synthesis of the desired product.
The method (II-2) is complicated because it includes a number of steps after the introduction of the C6 carbon chain.
The method (II-3) not only requires multi-stage steps for synthesizing Witig reagent and Horner-Emmons reagent, but also has the problems with respect to the yields of the products obtained by witig reaction and Horner-Emmons reaction.
The methods (III-1) and (III-3) require an expensive palladium catalyst.
The method (III-2) requires complicated steps for producing the silyl-substituted epoxy compound to be employed therein.